Identification of novel subgroup A variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus

Medical Research Council-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 464 Bearsden Road, Glasgow, UK

Abstract

Background

The development of anaemia in feline leukaemia virus (FeLV)-infected cats is associated
with the emergence of a novel viral subgroup, FeLV-C. FeLV-C arises from the subgroup
that is transmitted, FeLV-A, through alterations in the amino acid sequence of the
receptor binding domain (RBD) of the envelope glycoprotein that result in a shift
in the receptor usage and the cell tropism of the virus. The factors that influence
the transition from subgroup A to subgroup C remain unclear, one possibility is that
a selective pressure in the host drives the acquisition of mutations in the RBD, creating
A/C intermediates with enhanced abilities to interact with the FeLV-C receptor, FLVCR.
In order to understand further the emergence of FeLV-C in the infected cat, we examined
primary isolates of FeLV-C for evidence of FeLV-A variants that bore mutations consistent
with a gradual evolution from FeLV-A to FeLV-C.

Results

Within each isolate of FeLV-C, we identified variants that were ostensibly subgroup
A by nucleic acid sequence comparisons, but which bore mutations in the RBD. One such
mutation, N91D, was present in multiple isolates and when engineered into a molecular
clone of the prototypic FeLV-A (Glasgow-1), enhanced replication was noted in feline
cells. Expression of the N91D Env on murine leukaemia virus (MLV) pseudotypes enhanced
viral entry mediated by the FeLV-A receptor THTR1 while soluble FeLV-A Env bearing
the N91D mutation bound more efficiently to mouse or guinea pig cells bearing the
FeLV-A and -C receptors. Long-term in vitro culture of variants bearing the N91D substitution in the presence of anti-FeLV gp70
antibodies did not result in the emergence of FeLV-C variants, suggesting that additional
selective pressures in the infected cat may drive the subsequent evolution from subgroup
A to subgroup C.

Conclusions

Our data support a model in which variants of FeLV-A, bearing subtle differences in
the RBD of Env, may be predisposed towards enhanced replication in vivo and subsequent
conversion to FeLV-C. The selection pressures in vivo that drive the emergence of FeLV-C in a proportion of infected cats remain to be
established.